Stem cell transplantation: new approach 'protects from rejection'

Many patients who undergo stem cell transplantations run the risk that their immune system may reject the donor cells. But new research from the University of California-San Diego has detailed a new approach that may help tackle this problem. This is according to a study published in the journal Cell Stem Cell.

The research team, led by Yang Xu, says their findings may also provide researchers with a better understanding as to how tumors avert the immune system as they spread throughout the human body.

In collaboration with researchers from China, the investigators created "humanized" laboratory mice.

The mice had a functional human immune system that was able to effectively reject a large number of foreign cells that originated from human embryonic stem cells.

Using "humanized" mouse models with a functional human immune system, researchers found that a molecule combination called CTLA4-lg was able to protect cells derived from human embryonic stem cells from rejection.
Image credit: Zhili Rong, UC San Diego

The researchers explain that since human embryonic stem cells are "allogenic," meaning they differ from the body's own cells, a healthy human immune system will naturally attack the stem cells.

The study authors say that by overthrowing the immune system using immunosuppressant drugs, the body's "allogenic immune response" can be reduced, and that this method has proved successful for patients with terminal diseases that have undergone organ transplantation.

"But for stem cell therapies, the long term use of toxic immunosuppressant drugs for patients who are being treated for chronic diseases like Parkinson's disease or diabetes pose serious health problems," says Xu.

CTLA4-lg combination 'protects from immune rejection'

Using the humanized mouse models, the investigators tested various immune suppressing molecules, either alone or in combination.

From this, the researchers discovered that a combination of molecules - referred to as CTLA4-lg - were able to protect cells that originated from human embryonic stem cells from immune rejection.

The CTLA4-lg combination is made up of a drug that is already approved by the US Food and Drug Administration (FDA) to treat rheumatoid arthritis by curbing the T cells responsible for immune rejection, and PD-L1 - a protein that triggers immune resistance in tumors.

Explaining their discovery, Xu says:

"If we express both molecules in cells derived from human embryonic cells, we can protect these cells from the allogenic immune rejection.

If you have only one such molecule expressed, there is absolutely no impact. We still don't know exactly how these pathways work together to suppress immune rejection, but now we've got an ideal system to study this."

Potential to 'activate tumor immunity'

The investigators say their creation of the humanized mouse models and their findings could lead to the development of ways to switch on immune response to tumors, based on the fact that the molecules involved in the CTLA4-lg combination are known to cause tumors to bypass the immune system.

"You're dealing with the same exact pathways that protect tumors from our immune system," Xu explains.

"If we can develop strategies to disrupt or silence these pathways in tumors, we might be able to activate immunity to tumors. The humanized mouse system is really a powerful model with which to study human tumor immunity."

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